The invention relates to a new medical use for compounds which act as antagonists of 5-hydroxytryptamine (5-HT) at 5-HT3 receptors.
5-HT3 receptor antagonists may be identified by methods well known in the art, for example by their ability to inhibit 3-(5-methyl-1H-imidazole-4-yl)-1-[1-[3H]-methyl-1H-indol-3-yl]-1-propanone binding in rat entorhinal cortex homogenates (following the general procedure described by G Kilpatrick et al, Nature, 1987, 330, 746-748), and/or by their effect on the 5-HT-induced Bezold-Jarisch (B-J) reflex in the cat (following the general method described by A Butler et al, Br. J. Pharmacol., 94, 397-412 (1988)).
A number of different 5-HT3 receptor antagonists have been disclosed, for example those of group A: indisetron, Ro-93777, YM-114, granisetron, talipexole, azasetron, tropisetron, mirtazapine, ramosetron, ondansetron, lerisetron, alosetron, N-3389, zacopride, cilansetron, E-3620, lintopride, KAE-393, itasetron, mosapride and dolasetron.
In UK Patent No. 2209335, incorporated herein by reference, there is disclosed, inter alia, the compound 2,3,4,5-tetrahydro-5-methyl-2-[(5-methyl-1H-imidazol-4-yl)methyl]-1H-pyrido[4,3-b]indol-1-one, now known as alosetron, which may be represented by the formula (I): 
and pharmaceutically acceptable salts, solvates and pharmaceutically acceptable equivalents thereof, in particular its hydrochloride salt.
5-HT3 receptor antagonists are known to be useful in the treatment of a variety of conditions involving 5-HT3 receptor-mediated mechanisms, including in particular emesis.
Irritable bowel syndrome (IBS) is the most common diagnosis made by gastroenterologists (1) and is characterised by abdominal pain and discomfort and altered bowel functions (2-4). To date, no laboratory or structural defects have been identified in IBS and the formal diagnosis is based upon a constellation of symptoms defined by either the Manning (5) or Rome Criteria (6).
The current understanding of the pathophysiology or aetiology of IBS is limited, and no proven effective therapy is available (3,7). Moreover, many patients gain slight or even no relief from such therapies. Thus, there is a real need to develop new medicines for the treatment of IBS.
Over the last two decades compelling evidence has accumulated that a state of enhanced perception of visceral stimuli develops in patients with IBS (2,3,8-10). In balloon distension studies of the colon or rectum the threshold for sensation of pain is lower in IBS patients compared to controls, and this has been proposed as a biological marker for IBS (11). In view of the evidence for enhanced visceral perception in IBS and the frequent occurrence of pain, any agent considered to be of utility in the treatment of IBS should demonstrate effectiveness in the relief of pain.
Of the classes of therapeutic agents which have been proposed for the treatment of abdominal pain in IBS, 5-HT3 receptor antagonists are among the most promising. In animal models, these agents have been shown to decrease visceral pain responses (12,13). Furthermore, the 5-HT3 receptor antagonist, ondansetron, has been shown to slow colonic transit in normal volunteers (14-15). In patients with IBS ondansetron increases rectal compliance (16) and in diarrhoea-predominant IBS patients ondansetron improves stool consistency (17-19). Ondansetron also inhibits the contractile response of the colon in healthy volunteers in the early postprandial period (20), the time when many IBS patients experience symptoms. A second 5-HT3 receptor antagonist, granisetron, has also been shown to produce a decrease in rectal sensitivity, and reduce post-prandial motor activity in IBS patients (21).
Alosetron is a potent and selective 5-HT3 receptor antagonist, and in preliminary reports, alosetron has been shown to improve abdominal pain (22), and to slow colonic transit in IBS patients (23).
Surprisingly, it has now been found that 5-HT3 receptor antagonists represent a particularly effective and well tolerated therapy in nonconstipated female IBS patients.